Granulation process



Patented Feb. 6, 1951 GEANULATION Pnoonss Walter C. Gakenheimer,Westfield, N J1, assignorto Merck & (30., Inc., Railway, N. 1., acorpora-.

tion of New Jersey No Drawing. Application February 8, 1949, Serial No.75,283,

Sfllaims. 1

This invention relates to a method of granulation suitable for thepreparation of tablets.

The initial step in the preparation of tablets involves the conversionof the ingredients from a finely powdered to a granulated form. Aconventional method of. granulation, referred to as the moistgranulating process, consists of the addition to the powder mixtureof'moistening liquids, such as alcohol, water or acetone with a binderdissolved therein, causing the line particles to adhere and to remainadherent after dryin Bind r o u iorn WhiQll. ar pli m sed n ude sucrose.syru s. ela n. sp i mucilage of acacia, mucilage-of tragacanth, etc. Theuse of this method is, objectionable in many cases because of theinitial destructive effect of the solvent or the subsequent instabilityof the substances to; be compressed. The. process is likewise unsuitablefor mixtures, which are incompatiblein the presence of moisture.

An alternative method of granulation is that of preoonipression orslugging, Themixed ingredicuts, in finely powdered form, are compressedinto rather large discs or slugs which are. then broken and passedthrough a sieve of the proper size. Unsatisfactory resultsare obtainedif the ingredientseither possess poo;- compression qualities, or are ofa hygroscopic nature.

An object of this invention is to provide a new and improved process forthe granulation of substances which are either hydroscopic or can beslugged only with difficulty.

Another object of this invention is to provide a new and improvedgranulation process for the preparation of tablets of improvedstability. A

further object of thisinvention is to provide a granulation process forthe production of medicinal tablets that will retain their therapeuticpotencies for relatively long periods of time.

A still further object of this invention is to provide a new andimproved granulation process for the preparation of catalysts in tabletform suitable for industrial purposes.

Other objects and advantages will be readily apparent from the followingdisclosure.

It has been discovered that the granulation of finely,v divided materialmay be effected by the use of amixture consisting of an anhydrous halo,-genated non-polar solvent, together with a binder thatis solublev inthis solvent and also soluble in water. Themixture to be tableted ismixed with a solution of thewater soluble binding agent dissolved in thenon-polar solvent, the amount of binder used ranging. from 1-6%. of the,composite weight of the mixture. sufficientnon-spolar solvent. is usedto dissolve the binder therein and to convert the mixture to a dampnon-fluid mass. The moistened mass is forced through asieve, dried andsieved again. The size of the mesh used depends upon the size of thetablet to be. made.

soluble in both water and organic liquids, and

which have an average molecular weight of about 6000 to 7500. Thesesubstances resemble natural waxes in appearance and texture but aresoluble in a much wider range of solvents. In addition, Carbowax-GOOO isan excellent lubricant for the subsequent compression of the granulesinto.

tablets.

Inert substances such as sucrose, lactose, starch, etc, are commonlyadded when the mixtures to be tableted are insufficient to give a tabletof practical size; otherwise their use is unnecessary. A lubricant suchas stearic acid, or preferably a salt of this acid, such as magnesiumstearate, is well distributed finely divided form over the granulationprior to compression. The use of a lubricant insures uniform feedinginto the dies preventing' (a) malformations of the tablets caused bygranules adhering to the dies and punches after the compressionoperation, and lb) sticking of the punches.

A unique feature. in this. process, of particular and singularimportance in. the production of granulated, tableted and. extrudedcatalysts to be used in the. chemical and. petroleum industries, is thefact that the. final products contain a very low. percentagenf organicmaterial, as compared to the products made with conventional binderssuch assucrose, gelatin, acacia, tragacanth, etc. Likewise, anotherfeature is the maintenance of anhydrous. conditions throughout theprocess.

The method of this invention has been advantageously applied to thepreparation of various medicinal tabletsv including tablets of thiaminehydrochloride (Vitamin 131), tablets of Urecholine, tablets ofl-isoamidone, tablets of aspirin, phenacetin and caffeine, etc.Heretofore, these tablets could not be conveniently prepared by theconventional moist granulating process.

In addition, by using this special. granulating process, it has beenpossible to prepare tablets of therapeutic compositions such as ascorbicacid tablets, penicillin tablets, etc. which are completely soluble inwater, thereby facilitating the oral administration of these substancesto adults and infants as aqueous solutions or in combination withsoluble nutrients.

Likewise, the difilculties associated with. the production of stableeffervescent granules and tablets have been obviated by the use of mymethod. The resulting products are completely and rapidly solublepossessing none of the hygroscopic properties usually associated withthese types of products.

Granulated, tableted and extruded catalysts, including the catalystcommonly used in the synthesis of methyl alcohol, said catalystcontaining 50 mole percent each of chromic oxide and zinc oxide, havealso been prepared by this improved process.

It should be noted that the process of this invention can be used forthe preparation of tablets generally, and is not in any way restrictedor confined to tablets used for medicinal or therapeutic purposessolely.

The following examples illustrate the methods of carrying out thepresent invention, but it is to be understood that these examples aregiven by way of illustration and not of limitation.

Example 1 Tablets of thiamine hydrochloride containing the followingingredients were prepared as fol- The thiamine hydrochloride and lactosewere triturated in a mortar and then sifted through a #40 sieve. TheCarbowax-6000 was dissolved in the ethylene dichloride and this solutionwas added to the thiamine-lactose mixture with trituration. Afterthorough incorporation, the damp mass was pressed through a sieve andthe resulting granules were dried at 40 C. for 0.5 hour. The granuleswere then pressed through a #16 sieve.

The corn starch and magnesium stearate were triturated in a mortor andsifted through a #60 sieve onto the granulation. After thorough mixing,the granulation was compressed into 0.200 g. tablets.

In this and in the subsequent examples, the granules were compressedinto tablets of a Stokes F single punch tablet machine, punches ofvarious sizes being used to prepare tablets of different weights.

Example 2 Tablets of Urecholine containing the following ingredientswere prepared as follows:

The Urecholine and lactrose were thoroughly triturated in a mortar andthen moistened with the ethylene dichloride solution of Carbowax 6000.The mass was pressed through a #10 sieve and dried for 0.5 hour at 40 C.The dried granules were then pressed through a #16 sieve. The cornstarch and magnesium stearate were triturated together and siftedthrough a #60 sieve onto the granulation. After thorough mixing, thegranulation was compressed into tablets of 0.075 g.

Ebample 3 Tablets of l-isoamidone containing the following ingredientswere prepared as follows:

Per Per 1000 Tablet Tablets 1-Isoamidone hydrochloride monohydrate g-0.0050 5. 0 Lactoseg 0. 1400 140. 0 Sucrose .g 0. 0300 30.0OarbowaX-BOOO- g 0. 0040 4. 0 Ethylene dichloride. cc (35) Corn starchg- 0. 0200 20. 0 Magnesium stearate g 0. 0010 1.0

Example 4 Tablets of aspirin, phenacetin and caffeine containing thefollowing ingredients were prepared as follows:

Per Per 1000 Tablet Tablets Aspirin -g 0. 1050 195 Phenacetrm- .g 0.1300 Oaflcine g. 0. 0330 33 Carbowax-6000 g 0. 0040 4 Carbon tctrachlorcc (60) Gem starch g 0. 0130 13 Talc 0. 0230 23 Magnesium stearate g 0.0020 2 All ingredients were dried at 50 C. for 24 hours. The aspirin wasgranulated by mixing with it a solution of 2 g. of Carbowax-BOOO in 30cc. of carbon tetrachloride and pressing the moist mass through a #10sieve. The phenacetin and caffeine were thoroughly mixed and granulatedin the same manner with a solution of 2 g. of Carbowax-GOOO in 30 cc. ofcarbon tetrachloride. After drying the two lots of granules for 1 hourat 40 0., they were pressed separately through a #14 sieve. The cornstarch, talc and magnesium stearate were triurated together in a mortarand divided in half. One half was sifted through a #60 sieve onto theaspirin granulation, and the second half onto the phenacetincaifeinegranulation. The two separate granulated masses were then thoroughlymixed and compressed into 0.400 g. tablets.

1 Example 5' Tablets of Ascorbic Acid containing the followingingredients were prepared as follows: I

The. ascorbicv acid, citric acid, anhydrous dextrose and/1.0 g. of thecorn starch were triturated thoroughly ina. mortar. The CarbowaX-6000was dissolved in the ethylene dichloride, and this sol'utionwas addedtothemixed powders with trituration. After thorough incorporation, thedamp mass was pressed through a sieve, and the resulting granules weredried at C. for 0.5. hour. These granules were then broken down toproper size by first repressing through a #lcsieve andlthen through a#14 sieve. 5.0 g. of cornstarch was sifted onto the dried'granules (#60"sieve) and the lubricated granule mixture was tumbledifor. 0.5 hour toeffect mixing. The granules were then compressed into tablets weighing1.00'g. each.

These tablets, stored in. screw-capped glass jars at room temperaturefor 12 months, showed no loss in ascorbicacidcontent;

Example. 6.

Tablets of penicillin containing. the following ingredients wereprepared as follows:

The penicillin calcium was weighed out under low humidity conditions(less than 20% relative humidity) to protect the penicillin remaining inthe container. The following operations were carried out at a relativehumidity of 31% and at a temperature of 26 C. The penicillin calcium andsodium citrate were triturated in a mortar. The Carbowax-GOOO wasdissolved in the ethylene dichloride and this solution was added to: themixed powders with trituration. After thorough mixing, the damp mass waspressed through a #10 sieve, and the resulting granules were dried at 40C. for 0.5 hour. These granules were then broken down to proper size byfirst repressing them through a #10 sieve and then through a #14 sieve.The corn starch was sifted onto the dried granules with a sieve and alubricant granule mixture was tumbled for 0.5 hour to effect thoroughmixing. The granules were then compressed into tablets weighing 0.500 g.each.

These tablets, stored in screw-capped glass jars at room temperature for12 months, retained full therapeutic penicillin potency. '15

Example. 7

Effervescent tablets containing. the: following ingredients wereprepared aslfollows:

Pee Per Tablet; Tablets Citric acid, dried-at 55 0. M48 hrs; ..g 0.1084l 19. 0 Tartaric acid, dried at 55 C. for 48 hrs g 0. 1595 28. 0- Sodiumbicarbonate, dried at 55 O. for 48 hrs g; 0.8019. 53. 0 Carbowax-6000 go 0. 0302 5. 3 Ethylene dichloride cc (53) The following operations werecarried out at a relative humidity of 28% and at a temperature of 25? C.The citric acid andtartaric aciclWere triturated with a' mortar andpestle to a fine powder. 03' g. Carbowaxe6000 was dissolved insufiicient'ethylene dichloride. to make 8cc. of a solution, which wasadded to the dampacids: with trituration; After. thorough mixing; thedamp masswas pressed through a #10 sieve: and the resulting granuleswere dried at 40 C; for 05 hour; These granules were then blOkGHIdOWIIto proper size by first repressing them through a #10" sieve and thenthrough a #14 sieve.

The sodium bicarbonate was' granulated with asolution oi4;5 g. ofCarbowax-6000 in sufficient ethylene dichloride to make-4.5 cc. ofsolution. Tliis 'solution was added to the sodium bicarbonate ina mortarand after thoroughly incorporating the solution, the damp mass wasgranulated in a manneridentical to that described in the precedingparagraph.

The acid granules and the sodiumbicarbonate granules were combined andthoroughly" mixed by tumbling for 0.5- hour. Themixed' granules werecompressed without additional lubrication into tablets of 060g.

These tablets were stored in screw-cappedjars at room temperature for 12"months. At'the end of this period of time, there has been no change inphysical appearance or decrease in effervescence on addition to water;nor had there been any release of carbon dioxide in the glass jar;

Example. 8

Catalyst tablets containing the following ingredients were prepared asfollows:

Per Per 330 Tablet Tablets" Chromium-Dioxide; g 0. 3027 100. 0 ZincOxide g 0. 2460 81.4 Carbowax-.6000. l" .g 0.0060 1.8 Ethylenedichloride. l cc (30) T c g 0.0553 18.3

The following operations were carried out at 18% relative humidity and23 C; temperature. The chromium trioxide and zinc oxide were trituratedwith a mortar and a pestle to a fine powder. 1.8 g. of Carbowax-6000 wasdissolved in 30 cc. of ethylene dichloride, and this solution was addedto the oxides with trituration. After thorough mixing, the damp mass waspressed through a #10 sieve and the resulting granules were dried at 23C. for 4 hours. These granules were then broken down to proper size byrepressing them through a #16 sieve. 18.3 g. of talc was thoroughlymixedwith these granules by tumbling, and the mixture was compressed intotablets weighing 0.6100 geach.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the scope of theappended claims, they are to be considered as part of this invention.

I claim:

1. The process of preparing granules of therapeutic materials comprisingthe steps of mixing an active therapeutic agent, together with a solidwater-soluble polyethylene glycol dissolved in an anhydrous chlorinatednon-polar solvent said polyethylene glycol having a molecular weight ofabout 6000 to 7500, forming the moist nonfluid mass thus obtained intodiscrete granules and removing said non-polar solvent from saidgranules.

2. The process of preparing granules of therapeutic materials comprisingthe steps of mixing an active therapeutic agent, together with a -51"solid water-soluble polyethylene glycol dissolved in carbontetrachloride, said polyethylene glycol having a molecular weight ofabout 6000 to 7500, forming the non-fluid moist mass thus obtained intodiscrete granules and removing said carbon tetrachloride from saidgranules.

3. The process of preparing granules of therapeutic materials comprisingthe steps of mixing an active therapeutic agent, together with a solidwater-soluble polyethylene glycol dissolved in ethylene dichloride, saidpolyethylene glycol having a molecular weight of about 6000 to 7500,forming the damp non-fluid mass thus obtained into discrete granules andremoving said ethylene dichloride from said granules.

4. The process of preparing granules of therapeutic materials comprisingthe steps of mixing an active therapeutic agent, together with a solidWater-soluble polyethylene glycol dissolved in an anhydrous chlorinatednon-polar solvent, said polyethylene glycol having a molecular weight ofabout 6000 to 7500 and being present in the amount of about 1-6% of thecomposite weight of the mixture, and the amount of said non-polarsolvent being sufiicient to convert said mixture to a damp non-fluidmass, forming said moist nonfluid mass thus obtained into discretegranules by extrusion through apertures of fixed size and removing saidnon-polar solvent from said granules.

5. The process of preparing therapeutic tablets comprising the steps ofmixing an active therapeutic agent, together with a solid watersolublepolyethylene glycol dissolved in an anhydrous chlorinated non-polarsolvent, said polyethylene glycol having a molecular weight of about6000 to 7500 and being present in the amount of about 1-6% of thecomposite weight of the mixture, and the amount of said non-polarsolvent being suflicient to convert said mixture to a damp non-fluidmass, forming said moist nonfluid mass thus obtained into discretegranules by extrusion through apertures of fixed size,

removing said non-polar solvent from said granules and compressing saidgranules to form tablets.

6. The process of preparing thiamine hydrochloride tablets comprisingthe steps of mixing thiamine hydrochloride, together with a solidwater-soluble polyethylene glycol dissolved in an anhydrous chlorinatednon-polar solvent, said polyethylene glycol having a molecular weight ofabout 6000 to 7500, forming the moist non-fluid mass thus obtained intodiscrete granules, removing said non-polar solvent from said granules,lubricating said granules and compressing said granules to form tablets.

7. The process of preparing stable water-soluble ascorbic acid tabletscomprising the steps of mixing ascorbic acid together with a solidwatersoluble polyethylene glycol dissolved in an anhydrous chlorinatednon-polar solvent, said polyethylene glycol having a molecular weight ofabout 6000 to 7500, fOrming the damp non-fluid mass thus obtained intodiscrete granules, removing said non-polar solvent from said granules,lubricating said granules and compressing said granules to form tablets.

8. The process of preparing an eifervescent granule mixture whichcomprises mixing separately, the acid and basic constituents of saidmixture, together with a solid water-soluble polyethylene glycoldissolved in an anhydrous chlorinated non-polar solvent, saidpolyethylene glycol having a molecular weight of about 6000 to 7500,forming the damp non-fluid masses separately obtained into discretegranules by extrusion through apertures of fixed size, removing saidnon-polar solvent from said separate masses and mixing said dried acidand basic granules.

9. The process of preparing stable effervescent tablets comprising thesteps of mixing separately, the acid and basic constituents of saidmixture, together with a solid water-soluble polyethylene glycoldissolved in an anhydrous chlorinated nonpolar solvent, saidpolyethylene glycol having a molecular weight of about 6000 to 7500,forming the damp non-fluid masses separately obtained into discretegranules, removing said non-polar solvent from said separate masses,mixing said dried acid and basic granules, and compressing said mixtureof granules into tablets.

WALTER C. GAKENHEIMER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PA'I'ENTS Number Name Date 2,149,005 Bockmuhl Feb. 29,1939 2,195,596 Nitardy Apr. 2, 1940 OTHER REFERENCES McClelland,Chemical and Engineering News, vol. 23, Feb. 10, 1945, pages 247-50251.

1. THE PROCESS OF PREPARING GRANULES OF THERAPEUTIC MATERIAL COMPRISINGTHE STEPS OF MIXING AND ACTIVE THERAPEUTIC AGENT, TOGETHER WITH A SOLIDWATER-SOLUBLE POLYETHYLENE GLYCOL DISSOLVED IN AN ANHYDROUS CHLORINATEDNON-POLAR SOLVENT SAID POLYETHYLENE GLYCOL HAVING A MOLECULAR WEIGHT OFABOUT 6000 TO 7500, FORMING THE MOIST NONFLUID MASS THUS OBTAINED INTODISCRETE GRANULES AND REMOVING SAID NON-POLAR SOLVENT FROM SAIDGRANULES.